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US20090203737A1 - Pyrrole Derivatives as Positive Allosteric Modulators of Metabotropic Receptors - Google Patents

Pyrrole Derivatives as Positive Allosteric Modulators of Metabotropic Receptors Download PDF

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US20090203737A1
US20090203737A1 US11/920,490 US92049006A US2009203737A1 US 20090203737 A1 US20090203737 A1 US 20090203737A1 US 92049006 A US92049006 A US 92049006A US 2009203737 A1 US2009203737 A1 US 2009203737A1
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alkyl
oxadiazol
piperidin
fluoro
methanone
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Stefania Gagliardi
Emmanuel Le Poul
Iain Lingard
Giovanni Palombi
Sonia-Maria Poli
Jean-Philippe Rocher
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Addex Pharmaceuticals SA
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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Definitions

  • the present invention provides new compounds of formula I as positive allosteric modulators of metabotropic receptors—subtype 5 (“mGluR5”) which are useful for the treatment or prevention of central nervous system disorders such as for example, cognitive decline, both positive and negative symptoms in schizophrenia as well as other central or peripheral nervous system disorders in which the mGluR5 subtype of glutamate metabotropic receptor is involved.
  • the invention is also directed to pharmaceutical compounds and compositions in the prevention or treatment of such diseases in which mGluR5 is involved.
  • Glutamate the major amino-acid transmitter in the mammalian central nervous system (CNS), mediates excitatory synaptic neurotransmission through the activation of ionotropic glutamate receptors receptor-channels (iGluRs, namely NMDA, AMPA and kainate) and metabotropic glutamate receptors (mGluRs).
  • iGluRs ionotropic glutamate receptors receptor-channels
  • mGluRs metabotropic glutamate receptors
  • iGluRs are responsible for fast excitatory transmission (Nakanishi S et al., (1998) Brain Res Brain Res Rev., 26:230-235) while mGluRs have a more modulatory role that contributes to the fine-tuning of synaptic efficacy.
  • Glutamate performs numerous physiological functions such as long-term potentiation (LTP), a process believed to underlie learning and memory but also cardiovascular regulation, sensory perception, and the development of synaptic plasticity.
  • LTP long-term potentiation
  • glutamate plays an important role in the patho-physiology of different neurological and psychiatric diseases, especially when an imbalance in glutamatergic neurotransmission occurs.
  • the mGluRs are seven-transmembrane G protein-coupled receptors.
  • the eight members of the family are classified into three groups (Groups I, II & III) according to their sequence homology and pharmacological properties (Schoepp D D et al. (1999) Neuropharmacology, 38:1431-1476).
  • Activation of mGluRs lead to a large variety of intracellular responses and activation of different transductional cascades.
  • the mGluR5 subtype is of high interest for counterbalancing the deficit or excesses of neurotransmission in neuropsychiatric diseases.
  • mGluR5 belongs to Group I and its activation initiates cellular responses through G-protein mediated mechanisms.
  • mGluR5 is coupled to phospholipase C and stimulates phosphoinositide hydrolysis and intracellular calcium mobilization.
  • mGluR5 proteins have been demonstrated to be localized in post-synaptic elements adjacent to the post-synaptic density (Lujan R et al. (1996) Eur J. Neurosci. 8:1488-500; Lujan R et al. (1997) J Chem. Neuroanat., 13:219-41) and are rarely detected in the pre-synaptic elements (Romano C et al. (1995) J Comp Neurol. 355:455-69). mGluR5 receptors can therefore modify the post-synaptic responses to neurotransmitter or regulate neurotransmitter release.
  • mGluR5 receptors are abundant mainly throughout the cortex, hippocampus, caudate-putamen and nucleus accumbens. As these brain areas have been shown to be involved in emotion, motivational processes and in numerous aspects of cognitive function, mGluR5 modulators are predicted to be of therapeutic interest.
  • mGluR5 allele frequency is associated with schizophrenia among certain cohorts (Devon R S et al. (2001) Mol Psychiatry. 6:311-4) and that an increase in mGluR5 message has been found in cortical pyramidal cells layers of schizophrenic brain (Ohnuma T et al. (1998) Brain Res Mol Brain Res. 56:207-17).
  • mGluR5 The involvement of mGluR5 in neurological and psychiatric disorders is supported by evidence showing that in vivo activation of group I mGluRs induces a potentiation of NMDA receptor function in a variety of brain regions mainly through the activation of mGluR5 receptors (Mannaioni G et al. (2001) Neurosci. 21:5925-34; Awad H et al. (2000) J Neurosci 20:7871-7879; Pisani A et al (2001) Neuroscience 106:579-87; Benquet P et al (2002) J Neurosci. 22:9679-86).
  • mGluR5 is responsible for the potentiation of NMDA receptor mediated currents raises the possibility that agonists of this receptor could be useful as cognitive-enhancing agents, but also as novel antipsychotic agents that act by selectively enhancing NMDA receptor function.
  • NMDARs neuronal circuitry relevant to schizophrenia.
  • mGluR5 activation may be a novel and efficacious approach to treat cognitive decline and both positive and negative symptoms in schizophrenia (Kinney G G et al. (2002) 43:292).
  • mGluR5 receptor is therefore being considered as a potential drug target for treatment of psychiatric and neurological disorders including treatable diseases in this connection are Anxiety Disorders, Attentional disorders, Eating Disorders, Mood Disorders, Psychotic Disorders, Cognitive Disorders, Personality Disorders and Substance-related disorders.
  • the present invention relates to a method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR5 positive allosteric modulators.
  • FIG. 1 shows the effect of 10 ⁇ M of the example #1 of the present invention on primary cortical mGluR5-expressing cell cultures in the absence or in the presence of 300 nM glutamate.
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • (C 1 -C 6 ) means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • “(C 0 -C 6 )” means a carbon group having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C means a carbon atom
  • (C 1 -C 6 )alkyl includes group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl or the like.
  • (C 2 -C 6 )alkenyl includes group such as ethenyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 3-butenyl, 4-pentenyl and the like.
  • (C 2 -C 6 )alkynyl includes group such as ethynyl, propynyl, butynyl, pentynyl and the like.
  • Halogen includes atoms such as fluorine, chlorine, bromine and iodine.
  • Cycloalkyl refers to an optionally substituted carbocycle containing no heteroatoms, includes mono-, bi-, and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include on ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzo fused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene and the like.
  • Heterocycloalkyl refers to an optionally substituted carbocycle containing at least one heteroatom selected independently from O, N, S. It includes mono-, bi-, and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzo fused carbocycles. Examples of heterocycloalkyl include piperidine, piperazine, morpholine, tetrahydrothiophene, indoline, isoquinoline and the like.
  • Aryl includes (C 6 -C 10 )aryl group such as phenyl, 1-naphtyl, 2-naphtyl and the like.
  • Arylalkyl includes (C 6 -C 10 )aryl-(C 1 -C 3 )alkyl group such as benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 1-naphtylmethyl group, 2-naphtylmethyl group or the like.
  • Heteroaryl includes 5-10 membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur to form a ring such as furyl (furan ring), benzofuranyl (benzofuran ring), thienyl (thiophene ring), benzothiophenyl (benzothiophene ring), pyrrolyl (pyrrole ring), imidazolyl (imidazole ring), pyrazolyl (pyrazole ring), thiazolyl (thiazole ring), isothiazolyl (isothiazole ring), triazolyl (triazole ring), tetrazolyl (tetrazole ring), pyridil (pyridine ring), pyrazynyl (pyrazine ring), pyrimidinyl (pyrimidine ring), pyridazinyl (pyridazine ring), indolyl (indole ring),
  • Heteroarylalkyl includes heteroaryl-(C 1 -C 3 -alkyl) group, wherein examples of heteroaryl are the same as those illustrated in the above definition, such as 2-furylmethyl group, 3-furylmethyl group, 2-thienylmethyl group, 3-thienylmethyl group, 1-imidazolylmethyl group, 2-imidazolylmethyl group, 2-thiazolylmethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 1-quinolylmethyl group or the like.
  • solute refers to a complex of variable stoichiometry formed by a solute (e.g. a compound of formula I) and a solvent.
  • the solvent is a pharmaceutically acceptable solvent as water preferably; such solvent may not interfere with the biological activity of the solute.
  • “Optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.
  • substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
  • Preferred compounds of the present invention are compounds of formula I-A depicted below
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • Particularly preferred compounds of the present invention are compounds of formula I-B
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • the compound of this invention is represented by formula (I-D) or a pharmaceutically acceptable salt thereof
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • Another aspect of the invention are compounds of the formula II-A
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • Specifically preferred compounds are:
  • the present invention relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I or pharmaceutically acceptable carriers or excipients.
  • the present invention relates to a method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR5 allosteric modulators and particularly positive allosteric modulators.
  • the present invention relates to a method useful for treating or preventing peripheral and central nervous system disorders such as tolerance or dependence, anxiety, depression, psychiatric disease such as psychosis, inflammatory or neuropathic pain, memory impairment, Alzheimer's disease, ischemia, drug abuse and addiction.
  • peripheral and central nervous system disorders such as tolerance or dependence, anxiety, depression, psychiatric disease such as psychosis, inflammatory or neuropathic pain, memory impairment, Alzheimer's disease, ischemia, drug abuse and addiction.
  • compositions which provide from about 0.01 to 1000 mg of the active ingredient per unit dose.
  • the compositions may be administered by any suitable route. For example orally in the form of capsules, parenterally in the form of solutions for injection, topically in the form of unguents or lotions, ocularly in the form of eye-lotion, rectally in the form of suppositories.
  • the pharmaceutical formulations of the invention may be prepared by conventional methods in the art; the nature of the pharmaceutical composition employed will depend on the desired route of administration.
  • the total daily dose usually ranges from about 0.05-2000 mg.
  • the compound of formula I may be represented as a mixture of enantiomers, which may be resolved into the individual pure R- or S-enantiomers. If for instance, a particular enantiomer of the compound of formula I is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, this resolution may be conveniently performed by fractional crystallization from various solvents, of the salts of the compounds of formula I with optical active acid or by other methods known in the literature, e.g. chiral column chromatography.
  • Resolution of the final product, an intermediate or a starting material may be performed by any suitable method known in the art as described by Eliel E. L., Wilen S. H. and Mander L. N. (1984) Stereochemistry of Organic Compounds , Wiley-Interscience.
  • heterocyclic compounds of formula I can be prepared using synthetic routes well known in the art (Katrizky A. R. and. Rees C. W. (1984) Comprehensive Heterocyclic Chemistry , Pergamon Press).
  • the product from the reaction can be isolated and purified employing standard techniques, such as extraction, chromatography, crystallization, distillation, and the like.
  • the starting material amidoxime can be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis Scheme 1.
  • a nitrile derivative for example 4-fluoro-benzylnitrile
  • hydroxylamine under neutral or basic conditions such as triethylamine, diisopropyl-ethylamine, sodium carbonate, sodium hydroxide and the like in a suitable solvent (e.g. methyl alcohol, ethyl alcohol).
  • a suitable solvent e.g. methyl alcohol, ethyl alcohol.
  • the reaction typically proceeds by allowing the reaction temperature to warm slowly from ambient temperature to a temperature range of 70° C. up to 80° C. inclusive for a time in the range of about 1 hour up to 48 hours inclusive (see for example Lucca, George V. De; Kim, Ui T.; Liang, Jing; Cordova, Beverly; Klabe, Ronald M.; et al; J. Med.
  • the substituted amidoxime derivative (described in the Scheme 1) may be converted to an acyl-amidoxime derivative using the approach outlined in the Scheme 2.
  • PG 1 is an amino protecting group such as tert-Butyloxycarbonyl, Benzyloxycarbonyl, Ethoxycarbonyl, Benzyl and the like.
  • the coupling reaction may be promoted by coupling agents known in the art of organic synthesis such as EDCI (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide), DCC (N,N′-Dicyclohexyl-carbodiimide), in the presence of a suitable base such as triethylamine, diisopropyl-ethylamine, in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane).
  • EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
  • DCC N,N′-Dicyclohexyl-carbodiimide
  • a suitable base such as triethylamine, diisopropyl-ethylamine
  • a suitable solvent e.g. tetrahydrofuran, dichloromethane, N,N
  • a co-catalyst such as HOBT (Hydroxy-benzotriazole), HOAT (1-Hydroxy-7-azabenzotriazole) may also be present in the reaction mixture.
  • the reaction typically proceeds at a temperature in the range of ambient temperature up to 60° C. inclusive for a time in the range of about 2 hours up to 12 hours to produce the intermediate acyl-amidoxime.
  • the cyclisation reaction may be effected thermally in a temperature range of about 80° C. up to about 150° C.
  • the product from the reaction can be isolated and purified employing standard techniques, such as extraction, chromatography, crystallization, distillation, and the like.
  • the final step may be effected either by a process described in the Scheme 3 or by a process described in the Scheme 4.
  • protecting groups PG 1 are removed using standard methods.
  • B is as defined above
  • X is halogen, for example the piperidine derivative is reacted with an aryl or heteroaryl acyl chloride using method that are readily apparent to those skilled in the art.
  • the reaction may be promoted by a base such as triethylamine, diisopropylamine, pyridine in a suitable solvent (e.g. tetrahydrofuran, dichloromethane).
  • the reaction typically proceeds by allowing the reaction temperature to warm slowly from 0° C. up to ambient temperature for a time in the range of about 4 up to 12 hours.
  • protecting groups PG 1 are removed using standard methods.
  • the coupling reaction may be promoted by coupling agents known in the art of organic synthesis such as EDCI (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide), DCC (N,N′-Dicyclohexyl-carbodiimide) or by polymer-supported coupling agents such as polymer-supported carbodiimide (PS-DCC, ex Argonaut Technologies), in the presence of a suitable base such as triethylamine, diisopropyl-ethylamine, in a suitable solvent (e.g.
  • a co-catalyst such as HOBT (1-Hydroxy-benzotriazole), HOAT (1-Hydroxy-7-azabenzotriazole) and the like may also be present in the reaction mixture.
  • the reaction typically proceeds at ambient temperature for a time in the range of about 2 hours up to 12 hours.
  • the starting nitrile derivative is reacted with hydroxylamine under neutral or basic conditions such as triethylamine, diisopropyl-ethylamine, sodium carbonate, sodium hydroxide and the like in a suitable solvent (e.g. methyl alcohol, ethyl alcohol).
  • a suitable solvent e.g. methyl alcohol, ethyl alcohol.
  • the reaction typically proceeds by allowing the reaction temperature to warm slowly from ambient temperature to a temperature range of 70° C. up to 80° C. inclusive for a time in the range of about 1 hour up to 48 hours inclusive (see for example Lucca, George V. De; Kim, Ui T.; Liang, Jing; Cordova, Beverly; Klabe, Ronald M.; et al; J. Med.
  • the substituted amidoxime derivative (described in the Scheme 5) may be converted to an acyl-amidoxime derivative using the approach outlined in the Scheme 1.
  • PG 1 is an amino protecting group such as tert-Butyloxycarbonyl, Benzyloxycarbonyl, Ethoxycarbonyl, Benzyl and the like.
  • the coupling reaction may be promoted by coupling agents known in the art of organic synthesis such as EDCI (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide), DCC (N,N′-Dicyclohexyl-carbodiimide), in the presence of a suitable base such as triethylamine, diisopropyl-ethylamine, in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane).
  • EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
  • DCC N,N′-Dicyclohexyl-carbodiimide
  • a suitable base such as triethylamine, diisopropyl-ethylamine
  • a suitable solvent e.g. tetrahydrofuran, dichloromethane, N,N
  • a co-catalyst such as HOBT (Hydroxy-benzotriazole), HOAT (1-Hydroxy-7-azabenzotriazole) may also be present in the reaction mixture.
  • the reaction typically proceeds at a temperature in the range of ambient temperature up to 60° C. inclusive for a time in the range of about 2 hours up to 12 hours to produce the intermediate acyl-amidoxime.
  • the cyclisation reaction may be performed thermically by warming the reaction mixture without the purification of the acyl-amidoxime intermediate in a temperature range of about 80° C. up to about 150° C.
  • acyl-amidoxime can be isolated and purified employing standard techniques and then cyclised.
  • the cyclization reaction is typically carried out under basic condition such as triethylamine, diisopropyl-ethylamine, sodium carbonate, sodium hydroxide and the like in a suitable solvent (e.g. acetonitrile, dioxane).
  • the reaction typically proceeds in temperature range of about 80° C. up to about 150° C. for a time in the range of about 2 hours up to 18 hours.
  • the product from the reaction can be isolated and purified employing standard techniques, such as extraction, chromatography, crystallization, distillation, and the like.
  • the protecting group PG 1 is removed using standard methods.
  • B is as defined above, X is halogen or hydroxyl; for example the piperidine derivative is reacted with an aryl or heteroaryl acyl chloride using method that are readily apparent to those skilled in the art.
  • the reaction may be promoted by a base such as triethylamine, diisopropylamine, pyridine in a suitable solvent (e.g. tetrahydrofuran, dichloromethane).
  • the reaction typically proceeds by allowing the reaction temperature to warm slowly from 0° C. up to ambient temperature for a time in the range of about 4 up to 12 hours.
  • the coupling reaction may be promoted by coupling agents known in the art of organic synthesis such as EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), DCC (N,N′-dicyclohexyl-carbodiimide) or by polymer-supported coupling agents such as polymer-supported carbodiimide (PS-DCC, ex Argonaut Technologies), in the presence of a suitable base such as triethylamine, diisopropyl-ethylamine, in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane).
  • a suitable base such as triethylamine, diisopropyl-ethylamine
  • a suitable solvent e.g. tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane.
  • a co-catalyst such as HOBT (1-hydroxy-benzotriazole), HOAT (1-hydroxy-7-azabenzotriazole) and the like may also be present in the reaction mixture.
  • the reaction typically proceeds at ambient temperature for a time in the range of about 2 hours up to 12 hours.
  • the compounds of Formula I which are basic in nature can form a wide variety of different pharmaceutically acceptable salts with various inorganic and organic acids. These salts are readily prepared by treating the base compounds with a substantially equivalent amount of the chosen mineral or organic acid in a suitable organic solvent such as methanol, ethanol or isopropanol (see Stahl P. H., Wermuth C. G., Handbook of Pharmaceuticals Salts, Properties, Selection and Use , Wiley, 2002).
  • 0-1 min A: 95%, B: 5%
  • 11 min A: 0%, B: 100%
  • 11-12 min A: 0%, B: 100%
  • 12.1 min A: 95%, B: 5%
  • T 35° C.
  • UV detection Waters Photodiode array 996, 200-400 nm.
  • Method G Waters Alliance 2795 HT Micromass ZQ. Column Waters Atlantis C18 (75 ⁇ 4.6 mm, 3.0 ⁇ m). Flow rate 1.5 ml/min.
  • 0-0.5 min A: 95%, B: 5%
  • 5.5 min A: 0%, B: 100%
  • 5.5-8 min A: 0%, B: 100%
  • 8.1 min A: 95%, B: 5%
  • T 35° C.
  • UV detection Waters Photodiode array 996, 200-400 nm.
  • Method H UPLC system Waters Acquity, Micromass ZQ2000 Single quadrupole (Waters).
  • 0-0.1 min A: 95%, B: 5%
  • 9 min A: 0%, B: 100%
  • 9-12 min A: 0%, B: 100%
  • 12.1 min A: 95%, B: 5%
  • T 35° C.
  • UV detection Waters Photodiode array 996, 200-400 nm.
  • Method N HPLC system: Waters Acquity, MS detector: Waters ZQ2000.
  • Method Q Pump 1525u (Waters), 2777 Sample Manager, Micromass ZQ2000 Single quadrupole (Waters); PDA detector: 2996 (Waters).
  • Method S Pump 1525u (Waters), 2777 Sample Manager, Micromass ZQ2000 Single quadrupole (Waters); PDA detector: 2996 (Waters).
  • the microwave oven used is an apparatus from Biotage (OptimizerTM) equipped with an internal probe that monitors reaction temperature and pressure, and maintains the desired temperature by computer control.
  • the compound was prepared following the procedure described in the Example 1 (C), starting from (S)-3-[3-(1H-Pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (prepared as described in the Example 1(B)). The final compound was purified by preparative HPLC.
  • the compound was prepared following the procedure described in the Example 1(C), starting from (S)-3-[3-(1H-Pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (prepared as described in the Example 1(B)). The final compound was purified by preparative HPLC.
  • the resin was filtered off and washed repeatedly with dichloromethane; the filtrate was washed with HCl 1N (10 mL ⁇ 2 times), with NaOH 1N (aq.) (10 mL ⁇ 2 times) and with brine, then was dried over sodium sulphate and evaporated under reduced pressure.
  • the crude was purified by flash chromatography (silica gel, eluent: AcOEt/Hexane 7/3) to give 28 mg of (6-Fluoro-pyridin-3-yl)- ⁇ (S)-3-[3-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl ⁇ -methanone.
  • Triethylamine (0.96 mL, 6.89 mmol) and then ethyl chloroformate (0.69 mL, 7.23 mmol) were added dropwise at 0° C. to a solution of 1-Boc-piperidine-3-carboxylic acid (1.58 g, 6.89 mmol) in chloroform (10 mL), under nitrogen atmosphere. After stirring 10 min at 0° C., NH 3 (gas) was bubbled into the solution for 1 h. The reaction mixture was then stirred at room temperature for 3 h, 5% NaHCO 3 (aq) was added and the phases were separated. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to afford the title compound, which was used for the next step without further purification.
  • Phosphorus oxychloride (0.64 mL, 6.89 mmol) was added dropwise at 0° C. to a solution of 3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (1.58 g, 6.89 mmol) in pyridine (15 mL), under nitrogen atmosphere. After stirring overnight at room temperature, ethyl acetate was added and the solution was washed with 10% HCl (2 times). The phases were separated and the organics were dried over sodium sulphate and evaporated to dryness under reduced pressure.
  • the compound was prepared following the procedure described in the Example 5(F), starting from 3-[5-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine hydrochloride (prepared as described in the Example 5(E)). Purification of the final compound was performed by flash chromatography on silica gel (eluent: Hexane:AcOEt 1:1)
  • the compound was prepared following the procedure described in the Example 5(F), starting from 3-[5-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine hydrochloride (prepared as described in the Example 5(E)). Purification of the final compound was performed by flash chromatography on silica gel (eluent: Hexane:AcOEt 1:1)
  • the compound was prepared following the procedure described in the Example 8, using 4-fluoro-2-methyl-benzoic acid as acid of choice and starting from 3-[5-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine hydrochloride (prepared as described in the Example 5(E)). Purification of the final compound was performed by flash chromatography on silica gel (eluent petroleum ether/ethyl acetate 1:1)
  • Phosphorus oxychloride (812 ⁇ L, 8.72 mmol) was added dropwise at 0° C. to a solution of (S)-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (2 g, 8.72 mmol) in pyridine (20 mL), under nitrogen atmosphere. After stirring overnight at room temperature, ethyl acetate was added and the solution was washed with 10% HCl (2 times). The phases were separated and the organics were dried over sodium sulphate and evaporated to dryness under reduced pressure. The title compound was used for the next step without further purification.
  • Example 11 (A) The compound was prepared following the procedure described in the Example 10(E) starting from 3-[5-(1H-indol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (prepared as described in Example 11 (A)).
  • the compound was prepared following the procedure described in the Example 10(F), using 2-(3-piperidin-3-yl-[1,2,4]oxadiazol-5-yl)-1H-indole hydrochloride (prepared as described in the Example 11(B)). Purification of the final compound was performed by flash chromatography on silica gel (eluent: Hexane:AcOEt 6:4)
  • the compound was prepared following the procedure described in the Example 1 (B), starting from (S)-3-[3-(1H-indol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester.
  • the compound was prepared following the procedure described in the Example 1 (C), starting from 2-((S)-5-piperidin-3-yl-[1,2,4]oxadiazol-3-yl)-1H-indole hydrochloride. (2,4-difluoro-phenyl)- ⁇ (S)-3-[3-(1H-indol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl ⁇ -methanone was obtained pure after flash column chromatography (silica gel, eluent: AcOEt:petroleum ether 3:7).
  • the compound was prepared following the procedure described in the Example 5(F), using 3-[5-(2H-pyrazol-3-yl)-[1,2,4]oxadiazol-3-yl]-piperidine hydrochloride (prepared as described in the Example 13(B)). Purification of the final compound was performed by flash chromatography on silica gel (eluent: AcOEt:Hexane 3:1)
  • the compound was prepared following the procedure described in the Example 5(F), using 3-[5-(2H-pyrazol-3-yl)-[1,2,4]oxadiazol-3-yl]-piperidine hydrochloride (prepared as described in the Example 13(B)). Purification of the final compound was performed by flash chromatography on silica gel (eluent: AcOEt:petroleum ether 3:1)
  • the compound was prepared following the procedure described in the Example 1 (C), starting from 2-((S)-5-piperidin-3-yl-[1,2,4]oxadiazol-3-yl)-1H-indole hydrochloride (prepared as described in Example 12 (B)). (3,4-Difluoro-phenyl)- ⁇ (S)-3-[3-(1H-indol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl ⁇ -methanone was obtained pure after flash column chromatography (silica gel, eluent: AcOEt:petroleum ether 3:7).
  • Example 1 The compound was prepared following the procedure described in the Example 1 (C), starting from 2-((S)-5-piperidin-3-yl-[1,2,4]oxadiazol-3-yl)-1H-indole hydrochloride (prepared as described in Example 12 (B)).
  • (4-Fluoro-phenyl)- ⁇ (S)-3-[3-(1H-indol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl ⁇ -methanone was obtained pure after flash column chromatography (silica gel, eluent: AcOEt:petroleum ether 3:7).
  • Example 17(C) The title compound was obtained following the experimental procedure described in Example 17(C), starting from 3-[5-(1H-imidazol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine trifluoroacetate (prepared as described in Example 17(B)) and 3,4-difluorobenzoyl chloride. Purification was performed by trituration from diethyl ether to afford (3,4-difluoro-phenyl)- ⁇ 3-[5-(1H-imidazol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidin-1-yl ⁇ -methanone as a white solid.
  • the compound was prepared following the procedure described in the Example 4, starting from 2-((S)-5-Piperidin-3-yl-[1,2,4]oxadiazol-3-yl)-1H-indole hydrochloride (prepared as described in Example 12 (B)) and using 5-Methyl-isoxazole-4-carboxylic acid as the acid of choice.
  • ⁇ (S)-3-[3-(1H-Indol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl ⁇ -(5-methyl-isoxazol-4-yl)-methanone was obtained pure after flash column chromatography (silica gel, eluent: DCM).
  • the compound was prepared following the procedure described in the Example 4, starting from (S)-3-[3-(1H-Pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (prepared as described in Example 1 (B)) and using 5-Methyl-isoxazole-4-carboxylic acid as the acid of choice.
  • the compound was prepared following the procedure described in the Example 8, starting from ((S)-3-[5-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine hydrochloride (prepared as described in Example 10 (E)) and using 6-fluoro-pyridine-3-carboxylic acid as the acid of choice.
  • (6-Fluoro-pyridin-3-yl)- ⁇ (S)-3-[5-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidin-1-yl ⁇ -methanone was obtained pure after flash column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:1).
  • the compound was prepared following the procedure described in the Example 1(C), starting from ((S)-3-[5-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine hydrochloride (prepared as described in Example 10 (E)) and using 4-fluorobenzoyl chloride as the acylating agent.
  • (4-Fluoro-phenyl)- ⁇ (S)-3-[5-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidin-1-yl ⁇ -methanone was obtained pure after flash column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:1).
  • the compound was prepared following the procedure described in the Example 8, starting from 2-(3-piperidin-3-yl-[1,2,4]oxadiazol-5-yl)-1H-indole hydrochloride (prepared as described in Example 11 (B)) and using 6-fluoro-pyridine-3-carboxylic acid as the acid of choice.
  • the compound was prepared following the procedure described in the Example 8, starting from 2-(3-piperidin-3-yl-[1,2,4]oxadiazol-5-yl)-1H-indole hydrochloride (prepared as described in Example 11 (B)) and using 5-methyl-isoxazole-4-carboxylic acid as the acid of choice.
  • Phosphorus oxychloride (812 ⁇ L, 8.72 mmol) was added dropwise at 0° C. to a solution of (S)-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (2 g, 8.72 mmol) in pyridine (20 mL), under nitrogen atmosphere. After stirring overnight at room temperature, ethyl acetate was added and the solution was washed with 10% HCl (2 times). The phases were separated and the organics were dried over sodium sulphate and evaporated to dryness under reduced pressure.
  • the compound was prepared following the procedure described in the Example 1(C), starting from (S)-3-[3-(4-methyl-1H-pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine trifluoroacetate and using 4-fluorobenzoyl chloride as the acylating agent.
  • the final compound was purified by flash chromatography (silica gel cartridge, eluent gradient: from hexane/ethyl acetate 100:0 to hexane/ethyl acetate 60:40).
  • the compound was prepared following the procedure described in the Example 1 (C), starting from (S)-3-[3-(4-methyl-1H-pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine trifluoroacetate, prepared as described in Example 31 (E), and using 3,4-difluorobenzoyl chloride as the acylating agent.
  • the final compound was purified by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 100:0 to hexane/ethyl acetate 40:60).
  • the compound was prepared following the procedure described in the Example 28 (C), starting from (S)-3-[3-(4-methyl-1H-pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine trifluoroacetate, prepared as described in Example 31 (E), and using 6-fluoro-nicotinic acid as the acid of choice.
  • the final compound was purified by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 100:0 to hexane/ethyl acetate 0:100).
  • the compound was prepared following the procedure described in the Example 28 (C), starting from (S)-3-[3-(4-methyl-1H-pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine trifluoroacetate, prepared as described in Example 31 (E), and using 2-fluoro-isonicotinic acid as the acid of choice.
  • the final compound was purified by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 100:0 to hexane/ethyl acetate 1:1).
  • the compound was prepared following the procedure described in the Example 28 (C), starting from (S)-3-[3-(4-methyl-1H-pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine trifluoroacetate, prepared as described in Example 31 (E), and using 5-methyl-isoxazole-4-carboxylic acid as the acid of choice.
  • the final compound was purified by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 100:0 to hexane/ethyl acetate 1:1).
  • the title compound was prepared following the experimental procedure described in Example 1, starting from 1H-pyrrole-2-carbonitrile and using (R)-N-Boc-nipecotic acid. Purification of the final compound was performed by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 7:3 to hexane/ethyl acetate 1:1). The resulting colourless oil was triturated with diisopropylether to give (4-fluoro-phenyl)- ⁇ (R)-3-[3-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl ⁇ -methanone as a white solid.
  • the compound was prepared following the procedure described in the Example 1(C), starting from (S)-3-[5-(4-chloro-1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine hydrochloride, prepared as described in Example 39 (C), and using 4-fluorobenzoyl chloride as the acylating agent.
  • the final compound was purified by flash chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:2).
  • the compound was prepared following the procedure described in the Example 1(C), starting from (S)-3-[3-(4-chloro-1H-pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride, prepared as described in Example 43 (E), and using 4-fluorobenzoyl chloride as the acylating agent.
  • the final compound was purified by preparative HPLC.
  • the solid obtained after this purification was dissolved in acetonitrile and heated at 110° C. for 6 h, in a sealed tube, in a microwaves oven, then another heating cycle was performed (6 h, 130° C., microwaves). The solvent was evaporated under reduced pressure and the crude was purified by preparative HPLC.
  • the compound was prepared starting from 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloro-ethanone (prepared as described in Belanger; Tetrahedron Lett.; 1979; 2505-2508) according to the experimental procedures described in Examples 43 (A), 43 (B). 43 (C). 43 (D) and 43 (E).
  • the compound was prepared following the procedure described in the Example 1(C), starting from (S)-3-[3-(4-bromo-1H-pyrrol-2-yl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride, prepared as described in Example 45 (A), and using 4-fluorobenzoyl chloride as the acylating agent.
  • the final compound was purified by flash chromatography (silica gel, eluent: petroleum ether/ethyl acetate 7:3) and then by preparative HPLC.
  • the final compound was purified by flash chromatography (silica gel, eluent: DCM/MeOH 99:1) and then by preparative HPLC.
  • the solution was diluted with approx 50 mL of DCM then washed twice with 10% citric acid aqueous solution, then with water and with brine. The solution was dried over sodium sulphate and the solvent removed to give the product as a pale yellow oil.
  • Carbonyl diimidazole (340 mg, 2.1 mmol) was added to a solution of 4-fluoro-1H-pyrrole-2-carboxylic acid (230 mg, 1.78 mmol) in MeCN (10 mL) and stirred for 90 min. Concentrated NH 4 OH solution (2 mL) was added and the resulting mixture refluxed for 90 min. The solvent was removed, 10% citric acid solution (10 mL) was added and the solution extracted three times with EtOAc. The organic extracts were combined, dried over sodium sulphate and the solvent removed to give the product as a white solid.
  • the solution was washed with water, 10% citric acid solution and 5% NaHCO 3 solution, dried over sodium sulphate and the solvent removed to give a residue that was purified by flash chromatography (silica gel cartridge, eluent gradient: from hexane/ethyl acetate 100:0 to hexane/ethyl acetate 80:20).
  • the solid thus obtained was dissolved in acetonitrile (2 mL) and heated in a sealed tube at 75° C. for 90 min in a microwaves reactor.
  • Diisopropylazadicarboxylate (DIAD, 141 ⁇ L, 0.72 mmol) was added dropwise at 0° C. with stirring to a mixture of 5-(1H-pyrrol-2-yl)-2H-tetrazole (95 mg, 0.7 mmol), (4-fluoro-phenyl)-((R)-3-hydroxy-piperidin-1-yl)-methanone (100 mg, 0.36 mmol) and solid supported triphenylphosphine (PS-PPh 3 , ex Argonaut Technologies, loading 2.4 mmol/g, 420 mg, 1 mmol) in dichloromethane (4 mL). The mixture was heated in a sealed tube in a microwave reactor at 100° C.
  • the title compound was obtained pure as a colourless gum.
  • the solid thus obtained was dissolved in acetonitrile (2 mL) and heated in a sealed tube at 80° C. for 1 hour in a microwave reactor. The solvent was removed, the residue dissolved in EtOAc and washed twice with 5% citric acid solution, with 1M NaOH and with brine and the solvent removed. The residue was purified by flash chromatography (Biotage silica gel, eluted with EtOAc/hexane 10:90) to give the required product.
  • the compound was prepared as described in Tetrahedron, 1996, 1231-1234.
  • Example 1(C) The title compound was prepared following the experimental procedure described in Example 1(C), starting from (S)-3-[5-(4-fluoro-1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine hydrochloride, prepared as described in Example 60 (B), and using 4-fluorobenzoyl chloride as the acylating agent.

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US20090197897A1 (en) * 2005-05-18 2009-08-06 Addex Pharma Sa Novel Oxadiazole Derivatives and Their Use as Positive Allosteric Modulators of Metabotropic Glutamate Receptors
US20090215822A1 (en) * 2005-05-18 2009-08-27 Nikem Research Srl Substituted Oxadiazole Derivatives as Positive Allosteric Modulators of Metabotropic Glutamate Receptors
US20100004284A1 (en) * 2005-05-18 2010-01-07 Addex Pharma Sa Novel Heterocyclic Compounds as Positive Allosteric Modulators of Metabotropic Glutamate Receptors
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